Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation and in a humanized immunocompetent ARID1A mutant patient-derived OCCC mouse model. Our data indicate that inhibition of the mevalonate pathway simultaneously suppresses tumor cell growth and boosts antitumor immunity by promoting pyroptosis, which synergizes with ICB in suppressing ARID1A-mutated cancers. [Display omitted] •ARID1A inactivation sensitizes cells to pyroptosis•ARID1A regulates HMGCR and HMGCS1, rate-limiting enzymes of the mevalonate pathway•Statins suppress the growth of ARID1A-inactivated tumors via pyroptosis•Statins synergize with ICB in suppressing ARID1A-inactivated tumors Modulating the tumor immune microenvironment in a molecularly defined manner remains a major challenge. Zhou et al report a molecular mechanism of ARID1A regulated immuno-stimulatory cell death. The findings support that inhibition of the mevalonate pathway alone or in combination with immune checkpoint blockade represents an urgently needed therapeutic approach for ARID1A-mutated cancers.